Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[CH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH2:15][C:16]#[CH:17]
Reactant: C#CCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CCCN1CCNCC1
Yield: 95 %

Procedure:
To a solution of 23 (1.02 g, 5.47 mmol) triethylamine (762 μL, 5.47 mmol) and NaI (23 mg, 0.153 mmol) in DMSO but-3-ynyl mesylate (810 mg, 5.47 mmol) is dropwise added. The mixture is heated at 50° C. overnight, then water is added. The aqueous phase is treated with Et2O, and the organic phase is washed with brine, and dried over sodium sulfate. After solvent evaporation, 4-but-3-ynyl-piperazine-1-carboxylic acid t-butyl ester (24) (1.10 g, 4.62 mmol, 84%) is obtained as a yellow oil. 1H NMR (CDCl3, 200 MHz) δ 3.38 (t, J=4.8 Hz, 4H), 2.55 (m, 2H), 2.41-2.28 (m, 6H), 1.94 (t, J=2.6 Hz, 1H), 1.40 (s, 9H) ppm; 13C NMR (CDCl3, 50 MHz) δ 154.3 (s), 82.3 (s), 79.5 (s), 69.1 (d), 56.9 (t), 52.6 (t), 43.5 (t), 28.4 (q), 16.7 (t) ppm. Compound 24 (1.10 g, 4.62 mmol) is left reacting for 16 h in the presence of a 1:1 mixture of CH2Cl2/TFA (2 mL/mmol). After solvent evaporation, the residue is taken up in MeOH, and eluted through a column containing Amberlyst A-21, thus giving pure 1-but-3-ynyl-piperazine (25) (606 mg, 4.39 mmol) in 95% yield. 1H NMR (CDCl3, 200 MHz) δ 6.98 (br, 1H), 3.06-3.01 (m, 4H), 2.62-2.55 (m, 6H), 2.38-2.29 (m, 2H), 1.96 (t, J=2.6 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 82.1 (s), 69.4 (d), 56.6 (t), 50.6 (t), 44.1 (t), 16.8 (t). MS m/z 138 (M+, 7), 99 (100), 70 (48), 56 (98) ppm. To a solution of N,N′-di-Boc-N″-trifluoromethanesulfonylguanidine (1.52 g, 3.88 mmol) in anhydrous CH2Cl2 (18 mL) triethylamine (595 μL, 4.27 mmol) and 25 (590 mg, 4.27 mmol) are added. The mixture is left reacting for 16 h at room temperature, and then the solvent is evaporated. The residue is taken up in EtOAc and treated with a saturated aqueous NaHCO3 solution and brine. Crude product is purified by flash chromatography (CH2Cl2-MeOH 12:1, Rf=0.50), giving pure 5 as a white solid (1.10 g, 2.25 mmol) in 58% yield. 1H NMR (CDCl3, 200 MHz) δ 3.58 (m, 4H), 2.63-2.51 (m, 6H), 2.39-2.33 (m, 2H), 1.96 (t, J=2.6 Hz, 1H) ppm; 13C NMR (CDCl3, 50 MHz) δ 154.7 (s), 151.2 (s), 115.9 (s), 85.9 (s), 82.3 (s), 69.2 (d), 56.6 (t), 52.3 (t), 46.7 (t), 28.0 (q), 27.8 (q), 16.8 (t); MS m/z 380 (M+, 0.11), 160 (17), 121 (79), 57 (100) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([CH:21]([NH2:24])[CH2:22][CH3:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:21]([CH2:22][CH3:23])[CH2:19][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCC(N)CC
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC(CC)CC

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-ethyl-propylamine following general procedure B to afford 4-(1-ethyl-propylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (160 mg) following general procedure E.
Reaction SMILES: C([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[O:13])=[CH:7][CH:6]=1)(=O)C.C(Cl)(=O)C>CO.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[NH2:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([F:23])=[CH:18][CH:17]=3)=[O:13])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: CO
Product: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Temperature: 0 °C
Yield: 85 %

Procedure:
To a suspension of 0.6 g (1.43 mmol) of N-[6-(acetylamino)pyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.1, in 9 mL of anhydrous methanol, stirred at 0° C. under an inert atmosphere, are added dropwise 2.03 mL (28.54 mmol) of acetyl chloride. The reaction mixture is stirred at 0° C. for 30 minutes and then gradually brought to 70° C. and stirred for 48 hours. The reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 200 mL of saturated aqueous NaHCO3 solution and 200 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 0.46 g of the expected product is thus obtained.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][CH:16]([NH:15][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH2:19][OH:20]
Reactant: NC(CO)CO
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Solvent: CCO
Product: O=C(NC(CO)CO)c1cnc(C(=O)NC(CO)CO)cn1
Yield: 84.4 %

Procedure:
A solution of 392 mg of 2,5-dimethoxycarbonylpyrazine and 364 mg of 2-amino-1,3-propanediol in 5 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is filtered while hot. The white solid is washed with 3 times 10 cm3 of boiling ethanol. 530 mg of N,N′-bis(1,3-dihydroxy-2-propyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 218° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 3.45 to 3.65 (mt, 8H: 4×CH2O); 4.02 (mt, 2H: 2×NCH); 4.85 (t, J=5.5 Hz, 4H: 4×OH); 8.48 (d, J=9 Hz, 2H: 2×CONH); 9.25 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:7]([O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[N:6]=1)=[O:4].C[O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)=[C:27]([O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[N:26]=1)=[O:24].[OH-].[Na+]>C(O)C>[CH:18]1([CH2:17][O:16][C:7]2[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[CH2:19][CH2:20]1.[CH:38]1([CH2:37][O:36][C:27]2[N:26]=[C:25]([C:23]([OH:24])=[O:22])[CH:30]=[CH:29][C:28]=2[CH:31]2[CH2:35][CH2:34][CH2:33][O:32]2)[CH2:39][CH2:40]1
Reactant: COC(=O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Reactant: COC(=O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(C2CCCO2)c(OCC2CC2)n1
Product: O=C(O)c1ccc(C2CCOC2)c(OCC2CC2)n1
Yield: 100 %

Procedure:
A solution of 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid methyl ester (c1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid methyl ester (c2) (mixture from Example 114 c, 0.35 g, 1.3 mmol) and sodium hydroxide (55 mg, 1.4 mmol) in ethanol (50 mL) was heated to 90° C. for 2 h. The reaction mixture was evaporated, dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and the resulting precipitate was collected by filtration and dried in vacuo to give 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-3-yl)-pyridine-2-carboxylic acid (d1) and 6-(cyclopropylmethoxy)-5-(tetrahydrofuran-2-yl)-pyridine-2-carboxylic acid (d2) (mixture, d1:d2=3:2, 0.33 g, 1.3 mmol, 100%) as yellow solid; MS (EI): m/e=264.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH:21]=3)[C:16]([S:31]([CH3:33])=[O:32])=[CH:15]2)=[N:12][CH:13]=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][C:36]=1B(O)O>C(O)(CC)(C)C.O>[CH2:42]([O:41][C:38]1[CH:37]=[CH:36][C:35]([F:34])=[C:40]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])[CH:21]=4)[C:16]([S:31]([CH3:33])=[O:32])=[CH:15]3)=[N:12][CH:13]=2)[CH:39]=1)[CH3:43]
Reactant: CCOc1ccc(F)c(B(O)O)c1
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: CCOc1ccc(F)c(-c2cnc(-n3cc(S(C)=O)c4ccc(C(=O)N5CCOCC5)cc43)nc2)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (0.185 g, 1.34 mmol) and (Ataphos)2PdCl2 (0.032 g, 0.044 mmol) were added under an argon atmosphere to a solution of (1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)methanone (0.2 g, 0.445 mmol) and 2-fluoro-5-ethoxyphenylboronic acid (0.165 g, 0.89 mmol) in tert-amylalcohol (8.0 mL) and water (0.8 mL). The reaction mixture was stirred at 90° C. for 4 h, then cooled to ambient temperatures and filtered over celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica; dichloromethane with 2% methanol]. White solid. Yield: 0.14 g (62% of theory)
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Na+].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13].[C:15]([O:18][CH:19]=[CH2:20])(=[O:17])[CH3:16].O>CO>[C:15]([O:18][CH:19]=[CH:20][CH2:13][CH:12]([CH3:14])[CH:11]=[CH2:10])(=[O:17])[CH3:16]
Reactant: C=COC(C)=O
Reactant: C=CC(=C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(C)=O
Temperature: 100 °C

Procedure:
(p-Cymene)ruthenium dichloride dimer (27.8 mg, 0.091 mmol Ru) and sodium triflate (80 mg, 0.464 mmol) were dissolved in 10 ml of methanol. To the mixed solution were added isoprene (3 ml) and vinyl acetate (5 ml) and the mixture was stirred under heat at 100° C. for 14 hours. The resulting product was poured into water and extracted using toluene and the extract was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 10% and the ratio of an isomer being 17:3.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH3:25])=[C:19]2[C:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[S:29](=[O:37])(=[O:36])[NH:28][N:27]=1.Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CC#N.O.C(Cl)Cl>[C:43]([O:42][C:40](=[O:41])[CH2:39][N:21]1[C:22]2[C:18](=[CH:17][C:16]([F:15])=[CH:24][CH:23]=2)[C:19]([C:26]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29](=[O:36])(=[O:37])[N:28]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:27]=2)=[C:20]1[CH3:25])([CH3:46])([CH3:45])[CH3:44]
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1c(C2=NN(Cc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Benzyl bromide (10 μL, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([CH:24]=O)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10].[CH:26]([OH:29])([CH3:28])[CH3:27]>>[O:29]1[CH2:28][CH:26]1[CH2:27][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:8]=[CH:24][C:20]1[CH:21]=[CH:22][C:23]2[N:11]([CH2:9][CH3:10])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: NNc1ccccc1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Reactant: CC(C)O
Product: CCn1c2ccccc2c2cc(C=NN(CC3CO3)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
Phenylhydrazine (0.1 mole, commercially available from Aldrich, Milwaukee, Wis.) and 9-ethyl-3-carbazolecarboxaldehyde (0.1 mole, available from Aldrich Chemical, Milwaukee, Wis.) were dissolved in 100 ml of isopropanol in 250 ml 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was refluxed for 2 hours. Thin layer chromatography indicated the disappearance of the starting materials. At the end of the reaction, the mixture was cooled to room temperature. The 9-ethyl-3-carbazolecarbaldehyde phenylhydrazone crystals formed upon standing were filtered off and washed with isopropanol and dried in vacuum oven at 50° C. for 6 hours.
Reaction SMILES: [O-2].[Nd+3:2].[O-2].[O-2].[Nd+3].[Nd].[Cl-].[Nd+3].[Cl-].[Cl-].[CH2:11]([CH:13]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][O:15][P:16](=[O:27])([OH:26])[O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])[CH3:12].CC1CCCCC1>O>[CH2:11]([CH:13]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:14][O:15][P:16]([O-:27])([O:17][CH2:18][CH:19]([CH2:24][CH3:25])[CH2:20][CH2:21][CH2:22][CH3:23])=[O:26])[CH3:12].[Nd+:2]
Reactant: CCCCC(CC)COP(=O)(O)OCC(CC)CCCC
Reactant: [Nd+3]
Agent: [Cl-]
Agent: [Nd]
Agent: [O-2]
Solvent: O
Solvent: CC1CCCCC1
Product: CCCCC(CC)COP(=O)([O-])OCC(CC)CCCC
Product: [Nd+]
Reaction time: 5 h
Yield: 98 %

Procedure:
2.88 g of neodymium oxide containing 72.4% by weight of neodymium, 0.58 g of an aqueous solution of neodymium chloride containing 22.2% by weight of neodymium, 17.39 g of di(2-ethylhexyl)phosphoric acid (DEHPA) and 80 g of methylcyclohexane (MCH) are introduced into a reactor made inert beforehand with argon. The mixture is stirred and brought to 80° C. for 5 h. The mixture is cooled. Three washes with 20 g of water are successively carried out in order to remove the inorganic residues. Each wash comprises a step of stirring for 30 minutes and then a step of separating by settling out, also for 30 minutes, except for the final separating by settling out, which lasts 12 h. The water/MCH azeotrope is subsequently distilled with a Dean Stark apparatus. A clear solution of neodymium di(2-ethylhexyl)phosphate in MCH is thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:24][OH:25])[CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].C[CH2:27][C:28](=O)[C:29]([O-:31])=[O:30].B(F)(F)F.[CH3:37]COCC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:27][C:28]1([C:29]([O:31][CH3:37])=[O:30])[O:1][CH2:2][CH:3]([CH2:4][C:5]2[CH:23]=[CH:22][CH:21]=[C:7]([CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])[CH:6]=2)[CH2:24][O:25]1
Reactant: CCC(=O)C(=O)[O-]
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Reactant: CCOCC
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1(C)OCC(Cc2cccc(Cc3nc(-c4ccccc4)oc3C)c2)CO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To 5 ml of acetonitrile, 297 mg of 4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methylpyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47%) with stirring at room temperature, and stirred for 14 hours at room temperature. The reaction solution was poured into an ice-cold water solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:17][I:18]>CC(C)=O>[IH:18].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([S:11][CH3:17])=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC(C)CNC(=S)Nc1cc(Cl)cc(Cl)c1
Solvent: CC(C)=O
Product: CSC(=NCC(C)C)Nc1cc(Cl)cc(Cl)c1
Product: I
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A solution of 53 g of N-[3,5-dichlorophenyl]-N'-[2-methylpropyl]thiourea in 200 ml of acetone was heated under reflux. A total of 16 ml of methyl iodide was added dropwise, heating is continued for a further 3 hours after this addition. The reaction mixture was then cooled and the precipitate collected to give 50 g (55.5%) of N-[3,5-dichlorophenyl]-N'-[2-methylpropyl]-carbamimidothioic acid, methyl ester, hydroiodide, m.p. 150° C. Concentration of the mother liquors and recrystallization in ethanol/isopropyl ether afforded a further 20 g of the product. Total yield: 77%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[C@@:16]1([CH3:41])[N:21]=[C:20]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([CH3:38])([CH3:37])[S:18](=[O:40])(=[O:39])[CH2:17]1)(=O)=O.O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)[C:45]1[CH:50]=CC=C[C:46]=1P(C1C=CC=CC=1)C1C=CC=CC=1.C([Sn](CCCC)(CCCC)CCCC)C=C>CC#N.CC#N.Cl[Pd]Cl.CN(C=O)C>[C:26]([O:25][C:23](=[O:24])[N:22]([C:20]1[C:19]([CH3:37])([CH3:38])[S:18](=[O:40])(=[O:39])[CH2:17][C@:16]([C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[CH2:50][CH:45]=[CH2:46])([CH3:41])[N:21]=1)[C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2OS(=O)(=O)C(F)(F)F)CS(=O)(=O)C1(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2Oc2ccccc2P(c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=CCc1ccc([N+](=O)[O-])cc1[C@]1(C)CS(=O)(=O)C(C)(C)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1
Reaction time: 0.03 h
Yield: 468.5 %

Procedure:
100 ml RBF was charged with (R)-2-(5-((bis-(tert-butoxycarbonyl))amino)-3,6,6-trimethyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-nitrophenyl trifluoromethanesulfonate (794 mg, 1.204 mmol), bis(acetonitrile)palladium(II)dichloride (31.2 mg, 0.120 mmol), (oxydi-2,1-phenylene)bis(diphenylphosphine) (130 mg, 0.241 mmol) and DMF (6 ml). The mixture was stirred for 2 min until all solids dissolved. Allyltri-n-butylstannane (0.746 ml, 2.407 mmol) was added, the vial was sealed and stirred at 75° C. (heating block) for 30 min. The mixture was concentrated in vacuo and purified by FC on 40 g RediSep Gold column using 5-70% EtOAc in heptane to afford (R)-tert-butyl-N-(5-(2-allyl-5-nitrophenyl)-2,2,5-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl)-N-tert-butoxycarbonyl-carbamate (623 mg, 1.129 mmol, 94% yield). LC/MS (ESI+) m/z=574 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[OH-].[NH4+].[CH3:19]O>>[NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:19])=[O:7]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)c(O)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)c1ccc(N)cc1O
Temperature: 70 °C
Yield: 60 %

Procedure:
To a suspension of 9.18 g (0.06 mole) 4-aminosalicylic acid (7) (Aldrich A7,960-4) in 40 mL of dry methanol was added 8 mL of concentrated sulfuric acid slowly. The mixture was heated under reflux at 70° C. for 1.5 hours and then it was cooled in an ice-water bath. Enough concentrated ammonium hydroxide solution was added to adjust the pH to 9 and the precipitate was filtered, rinsed with water and dried to give 6.01 g (60%) of 9 as a solid, mp 118-120° (ref. 120-121°). Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: [C:1]1([S:7]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][OH:19].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:17]1[CH2:18][O:19][C:12]2([CH2:13][CH2:14][CH2:15][CH:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)[O:16]1
Reactant: OCCO
Reactant: O=C1CCCC(S(=O)(=O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)C1CCCC2(C1)OCCO2
Yield: 97 %

Procedure:
To a solution of 5.3 g of 3-(phenylsulfonyl)-cyclohexan-1-one in 60 ml of benzene, were added 0.3 ml of 1,2-ethanediol and 0.2 g of anhydrous paratoluenesulfonic acid. The reaction mixture was heated under reflux for 4 hours. After the reaction, a 2M aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate three times. The combined organic layers were washed with saturated saline and then, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl ether, whereby 6.1 g of 1,1-(ethylenedioxy)-3-(phenylsulfonyl)-cyclohexane (m.p.: 93–95° C.) were obtained in the form of white crystals. Yield: 97%
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:26]([O-])([N+]([O-])=O)=[O:27]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:26]=[O:27])[C:5]([N:7]([CH2:17][CH:18]=[CH2:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 65.4 %

Procedure:
3.2 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-(2-propenyl)-3-L-arabinopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](OS(C(F)(F)F)(=O)=O)=[N:16]2)=[CH:11][CH:10]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:30]=2[N:31]=1.Cl.C(N(CC)C(C)C)(C)C.COCC(O)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:36][C:33]3[CH:34]=[CH:35][C:29]4[O:28][C:27]([CH3:26])=[N:31][C:30]=4[CH:32]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: COc1ccccc1-c1ccc2cnc(OS(=O)(=O)C(F)(F)F)nn12
Agent: Cl
Solvent: COCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4oc(C)nc4c3)nn12

Procedure:
The Title compound was prepared in the following manner: A mixture of Trifluoro-methanesulfonic acid 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl ester (100 mg, 0.3 mmol), 2-Methyl-benzoxazol-5-ylamine; hydrochloride (100 mg, 0.5 mmol), N,N-Diisopropylethylamine (2 mL, 10 mmol), and 1-Methoxy-2-propanol (0.3 mL, 3 mmol) were heated at 80° C. overnight. The reaction was concentrated, filtered and placed onto the Gilson. The pure fractions were lyophilized to give a yellow solid (30 mg, 20%). LCMS (E/I+) 372 (M+H). NMR 1H (DMSO-d6)-9.5 (s, 1H), 9.0 (s, 1H), 8.2 (s, 1H), 7.78 (d, 1H, J=7.80 Hz), 7.45-7.54 (m, 3H), 7.23 (d, 1H, J=8.26), 7.12 (t, 1H, J=7.51 Hz), 6.92-6.96 (m, 2H), 3.84 (s, 3H), 2.58 (s, 3H).